Integrins play central roles in cell adhesion and tissue formation, in cell and tissue movements, and in the regulation of gene expression, cell growth, and the cytoskeleton. Successful coordination and spatial organization of cellular structures and molecules associated with integrins, such as adhesion sites, the intracellular actin-based cytoskeleton, and signal transduction systems, appear to be crucial during key steps in embryonic development, wound healing, and differentiated tissue function. We are characterizing the mechanisms of integrin signaling and function. Using natural ligands, synthetic peptides, monoclonal antibodies, and intermolecular chimeras, distinct biological roles are being identified for integrin occupancy by ligand versus integrin aggregation, as well as synergistic effects of both together, in further combination with tyrosine phosphorylation. Roles of integrin receptors are also being elucidated in controlling growth factor receptor location, intracellular signal transduction, and associations of different classes of cytoskeletal molecules. A hierarchy of cytoplasmic responses was identified by analyses of the requirements for controlling the localization of specific molecules. Mechanisms of integrin regulation of signal transduction via the MAP kinase pathway are being explored. A molecular mechanism for integrin-growth factor synergism has been identified. A variety of chimeras containing individual cytoskeletal and signal transduction molecules are being tested as mediators of downstream steps in this hierarchy of responses to integrin receptors. Characterization of these distinct biological steps is generating novel tools for understanding the transmembrane spatial control of adhesion/signaling complexes that are essential for coordinating the complex rearrangements and final organization of oral, facial, and other developing tissues. Because alterations in integrin function may contribute to a variety of human congenital defects and affect wound healing, these studies also provide an opportunity to identify new pathways as potential targets for diagnosis and therapy.